Brain dysfunction is one of the most common organ failures in severe sepsis, and is associated with higher risk of mortality and development of cognitive impairment among survivors. Although the mechanisms underlying these associations are not entirely understood, evidence suggests that sepsis results in brain injury ultimately leading to cell death and lasting damage to key brain regions. However, the diagnosis of brain injury in sepsis is challenging. The frequent need for deep sedation, mechanical ventilation and cardiovascular support presents a major barrier to the early detection of brain injury using common methods such as neurologic exam or neuroimaging. Higher plasma levels of neuron specific enolase (NSE), a marker of neuronal injury, are associated with worse outcomes following traumatic and anoxic brain injury, leading to our hypothesis that NSE levels will be associated with mortality and cognitive outcomes in severe sepsis. The broad objectives of the proposed project are to: 1) determine the association of plasma NSE concentration at intensive care unit (ICU) admission with the risk of mortality in patients with severe sepsis, 2) determine the association of plasma NSE concentration at ICU admission with cognitive function at hospital discharge in patients with severe sepsis, 3) train the candidate in measurement of cognitive function following critical illness, biomarker measurement and analysis, neuroinflammatory and neuroimmune pathways that result in neurodegeneration, cohort study design and management, advanced epidemiologic concepts, biostatistical methods for the analysis of competing risks, and 4) provide the candidate with individualized mentoring to ensure his continued development into an independent patient-oriented researcher. The candidate will use two well-developed ongoing cohorts of critically ill patients with severe sepsis Clinical data is collected prospectively, plasma samples are drawn at ICU admission, and patients undergo cognitive assessment at hospital discharge. NSE levels will be measured in admission plasma samples and tested for an association with mortality and cognitive function. The candidate will complete these objectives while engaging in a rigorous training program which will include: 1) didactic coursework, 2) mentoring by a senior investigator with expertise in neuroinflammatory processes and neurocognitive disorders, and 3) mentoring by a senior investigator trained in epidemiologic and translational critical care research. Moreover, the results of this proposed project will direct future research in the diagnosis of brain injury and te mechanisms by which severe sepsis results in brain injury.